A prevailing dogma of leptin research field has attributed the regulation of body weight by leptin exclusively to the hypothalamus of central nervous system (CNS). Here, we demonstrate and propose to further evaluate a genetic example that leptin regulates body weight by DIRECT regulation of fat metabolism in adipocytes in addition to its functions in the hypothalamus. Recently, using a Technical Knock-out (TKO) system, we have engineered a mouse model to display adipocyte-selective deficiency of the leptin receptors. These mutant mice are hereafter referred to as TKO-OBR mice, short for technical knockout of OB-receptors. TKO-OBR mice maintained normal levels of leptin receptors in the hypothalamus. However, the mutant mice developed increased adiposity, hyperinsulinemia, hypertriglyceridemia, impaired glucose tolerance and insulin sensitivity, as well as elevated triglyceride levels in livers and skeletal muscle. A variety of genes involved in regulating fat and glucose metabolism are dysregulated in the white adipose tissue of the mutant mice, such as TNFalpha, AdipoQ, leptin, fatty acid synthase, SREBP-1, glycerol kinase, and beta3-adrenergic receptor. Furthermore, the mutant mice are significantly more sensitive to high-fat feeding with regards to developing obesity and severe insulin resistance than their wild-type littermates. In summary, we have provided the first unequivocal genetic example demonstrating the physiological importance of a direct peripheral effect of leptin in vivo. In this application, we propose a series of studies to further understand the molecular mechanisms by which leptin regulates adiposity and insulin sensitivity through its direct actions in adipocytes. We believe that these studies will provide a possible molecular linkage between adipocyte-selective leptin receptor deficiency and type 2 diabetes.